Neoplasia II-III study notes
General
- tumors are overgrowths, clones within clones, of cells bearing cumulative genetic injuries which each confer growth advantages over their neighbors
- oncogenes are slightly altered (activated) versions of normal, housekeeping genes (proto-oncogenes); activation may occur by point mutation, translocation, or increased copy number (amplification)
- oncogenes tell the cell to divide when it shouldn't
- anti-oncogenes are normal genes that tell cells when not to divide; when both copies are damaged or missing, the neoplastic phenotype may be expressed
- viruses cause cancer by 1) binding and inactivating the products of normal anti-oncogenes; 2) increasing cell turnover, allowing selection of abnormal clones; 3) scrambling the genome
- cancer of the cervix and hepatocellular carcinoma are the most important cancers caused by known infectious agents
Attributes of cancer cells
- carcinogenesis is a generic term for a series of events leading up to expression of full malignant potential
- tumors are clonal overgrowths
- each successive mutation confers an unfair growth advantage the cell line which bears it
- as the tumor grows, non-disjunction creates cells with extra chromosomes and many cancers become aneuploid
- growth fraction is the percent of cells making nucleic acid as a given time - monoclonal antibody Ki-67 stains proliferating cells
- increased numbers of mitotic figures seen in cancer represent mitoses that got stuck because of the cell disorganization
- ability to spread and grow
- mechanism of metastasis involve binding of laminin of basement membranes, and destruction of type IV collagen in basement membrane
- a tumor must be able to induce its own blood supply - the factor is VEGF
- altered growth properties
- relatively unregulated proliferation
- failure to mature
- transplantability
- immortality
- loss of contact inhibition
- loss of serum and anchorage requirement
- loss of density-dependent growth inhibition
- karyotypic changes
- many cancers have chromosomal abnormalities that are characteristic for that particular tumor, and it seems likely that we will eventually discover one or more such changes
- t(9, 22) - chronic myelogenous leukemia
- t(8, 14) - Burkitt's lymphoma
- del 3p - renal cell and oat cell carcinoma
- del 13q - retinoblastoma
- del 11p - Wilms tumor
- monosomy 22 - meningioma
- antigenic changes
- all tumors evoked by a specific oncogenic retrovirus tend to have the same tumor-specific antigens
- tumors induced by a specific chemical are all pretty much different antigenically
- metabolic - old ideas about cancer focused on increased aerobic metabolism
- cell surface and membrane changes
- typical changes include greatly increased lectin agglutinability, loss of such adaptations as microvilli and pseudopods, increased turnover of plasma membrane
Chemical Carcinogenesis
- classic carcinogenesis experiments disclosed that key steps are often the induction and promotion of cancer by chemicals
- the Delaney Clause forbids the presence of any cancer-producing chemical in any concentration in U.S. food
- soot - cancer of srotum
- cancer chemoRx - acute leukemia
- cyclophosphamide - transitional epithelial cancers
- other alkylaters - many cancers
- polycyclic HC's - tobacco-smoking related cancers
- Azo dyes - bladder cancer
- aflatoxin - eaters of moldy grans and peanuts
- betel nut - mouth and throat cancer
- pickled fish - Chinese nasopharyngeal cancer
- pickled vegetables - Chinese esophageal cancer
- vinyl chloride - angiosarcoma of the liver
- chromium, nickel - lung cancer
- cadmium - prostate cancer
- asbestos - lung cancer, mesothelioma
- arsenic - skin cancers
- PCB's - pollutants, cause human cancer
- saccharin - bladder cancer
- cyclamates - bladder cancer
- human feces - several, including bile salts
- benzene - leukemias and related problems
- phenacetin - transitional epithelial cancers
- anabolic steroids - liver cancer
- estrogen - endometrial hyperplasias and carcinomas
- ferric ion - liver cancer
- some environmental carcinogens are direct-acting and exert their effect directly; however the majority (procarcinogens) require metabolic conversion (activation) to produce carcinogenic forms (ultimate carcinogens)
- heavy metals depolymerize DNA
- often the carcinogen is activated by the hepatic P-450 mixed function oxidase system
- the actual carcinogen either damages DNA directly or is a potent electrophile
- the most dubious carcinogen right now is high power electric lines
- initiation - the result of exposure of a cell or cells toa carcinogen, which permanently alters its genetic material but not its phenotype
- promotion - a substance that causes initiated cells to turn into tumors; tumors result when the promoter is administered after initiation
- the classic promoters have in common the ability to activate protein kinase C, the part that regulates mitosis
- probably many things work by disrupting normal tissue homeostasis; hepatits B and C viruses are much more likely to produce hepatocellular carcinoma when they cause rapid, prolonged cell turnover
- a complete carcinogen is a substance that is both initiator and promoter
- the Ames test for mutagenicity relies on production of mutants in a culture of typhoid bacteria
Radiation Carcinogenesis
- exposure to high energy photons is a cause of cancer
- atomic bomb, Chernobyl's children
- occupational radiation carcinogenesis
- iatrogenic radiation carcinogenesis - x-rays, radiophosphorus
- ultraviolet radiation is the principle risk factor in most skin cancers
Oncogenic Viruses
- viral causation of cancer is well-documented in the lab, and is important in some human cancers
- polyoma virus and SV40 are linked to a variety of animal tumors
- mouse mammary tumor virus is transmitted from mother to child in the milk
- wart virus (HPV) cuase warts in humans, and certain strains also cause cancer of uterine cervix in humans
- Epstein-Barr virus is necessary to cause African Burkitt's lymphoma, and is etiologic in Chinese nasopharyngeal cancer, and immunoblastic lymphoma
- Hepatits B virus is a major cause of hepatocellular carcinoma
- HTLV-I causes epidemic leukemia in Japanese humans
Other reputed carcinogens
- foreign body carcinogenesis and carcinogenesis by repeated trauma are possibilities
- there is speculation that connecting carcinogenesis and prognosis of cancers to mental attitudes
Oncogenes
- oncogenes are DNA sequences within eukaryotic cells that seem to be involved in the development and maintenance in tumors
- oncogenes are slightly altered forms of proto-oncogenes which are essential genes that govern normal tissue growth and differentiation
- many proto-oncogenes are the genes for hormone or vitamin receptors or the proteins to which they talk, while others seem to be general turn-ons
- oncogenes were originally discovered in transforming retroviruses
- retroviruses are ubiquitous, generally harmless RNA viruses; the RNA code is transcribed onto DNA, which is then integrated into the host genome
- viral oncogenes turned out to be cnacer-producing genes that the viruses had just happened to pick up while growing in established tumors
- a viral oncogene is a proto-oncogene minus its regulatory sequences, or with a characteristic mutation, or in an excessive number of copies; they are capable of causing cancer themselves and hence are very different from their normal counterparts
- a proto-oncogene that has aquired the ability to cause cancer is said to be activated
1) classic tyrosine kinase proto-oncogenes
- these are signal-transducers, across membranes
- c-abl is translocated from chromosome 9 to the breakpoint cluster region of chromosome 22 in most cases of chronic myelogenous leukemia, and this is part of the Philadelphia chromosome phenomenon
2) GTP-binding protein proto-oncogenes
- includes the ras family
- their protein products are apparently the signal-transducing G-proteins that modulate various transmembrane signals
- each codes for a p21 protein that binds GTP, and the healthy ones hydorlyze it
- most oncogenic ras are mutations with a single base pair change that alters an amino acid at position 12, 13, or 61 in the protein product
- this destroys GTP-ase activity but retains GTP-binding activity, and current thinking is that these stay locked on, telling the transforming cell to keep dividing
- ras oncogenes probably help cause a large precentage of human cancers; around 40% of human colon dysplasias and adenocarcinomas have mutations in codon 12 of K-ras; a new mutation at codon 13 of N-ras heralds transformation of myelodysplastic syndrome to leukemia
3) DNA binding protein proto-oncogenes
- this is the myc family, present in all eukaryotes, whose protein products are intranuclear and bind to DNA itself; they enable DNA synthesis
- myc activation is usually by amplification and/or translocation rather than by mutation
- in Burkitt's lymphoma of B-cells, c-myc is moved next to the immunoglobulin gene; the cell decides to multiply like crazy every time it is told to make antibodies
- myc genes are much amplified in nueroblastomas and oat cell lung carcinomas
- myb is a related proto-oncogene involved both in human cancer and in the proliferation of cells in human atheromas
4) Growth factos protein proto-oncogenes
- the prototype in c-sis, which codes for the beta chain of platelet-derived growth factor, the stuff that tells fibroblasts to divide in wound healing
- probably sis-induced cancers grow by autocrine self-stimulation by PDGF; PDGF is greatly over-expressed in many sarcomas, and only transforms cells with the PDGF receptor
- the sis product also seems to be important in induction of stroma by tumors
5) Protein growth factor receptor proto-oncogenes
- this includes erbB, which codes for a protein homologous to the epidermal growth factor receptor, and fms, which codes for macrophage colony-stimulating factor
- the erbB gene product lies across the cell membrane; epidermal growth factor binds to the outer portion, while the inner portion is a tyrosine kinase that cleaves phosphatidyl-inositol 4,5 diphosphate into inositol triphosphate and diacylgylcerol; these two substances have multiple effects on intracellular control systems, mostly turn-ons
- erbB mutants are those that are locked in the on position, and erbB related cancers are mostly squamous cell carcinomas, and fms related cancers are mostly hematopoietic cancers; erbB is amplified in a large percentage of malignant melanomas
- the related neu is amplified in many carcinomas, notably adenocarcinomas, especially of the breast, and the degree of amplification strongly correlates with bad outcome
6) Enhancer binding protein proto-oncogene
- erbA codes for the human thyroid hormone receptor; linked to a variety of animal cancers
7) Transcription initiation factor proto-oncogenes
- jun is the factor that initiates transcription of DNA at a particular sequence
8) Master switch proto-oncogenes
- fos apparently turns short-term stimulation into long-term differentiation, and fos mutants help immortalize cell cultures
9) left overs - ocogenes that do not yet fit into any families
- int-2 - gene for fibroblast growth factor 3; relative to flg and bck (FGF2)
- bcl-2 - activated in most B-cell lymphomas, and its relative bcl-X, tell the cell not to undergo apoptosis but to divide if told to do so
- p16 - cyclin dependent kinase inhibitors; cyclin D1 itself is involved in the lymphoma translocation, and is amplified in around 20% of breast cancers, and the knockout mice get breast tumors
- a subject that will probably soon be important in the activation of genes that enable cancer cells to metastasize
Anti-oncogenes
- keep cells benign, even when the oncogenes are activated; to lose their anti-cancer effect, both copies must be altered
- Knudson's Law for anti-oncogenes
- one hit - you have a cell with a much increased propensity to turn malignant
- two hit - you have a cancer cell
- if the malignant phenotype requires both copies to be bad, it is autosomal recessive
- retinoblastoma
- autosomal dominant trait
- believed to be the result when a mutation damages both copies the healthy anti-oncogene in a single cell; the cell now lacks any copy of the anti-oncogene, and is transformed
- locus is RB1 at 13q14; oat cell carcinomas become homozygous for defects here, and the loss of this anti-oncogene causes more rapid growth
- the most common genetic injury in human cancer is damage to the p53 gene
- the p53 gene, when defective, is now strongly linked to all human cancers
- the p53 gene product is a sequence specific binder to DNA that prevents mitosis during times of cell injury, so that there will be more times of cell injury, so that there will be more time for DNA repair
- a famous link to hepatocellular carcinomas
- the anti-oncogene p53 product is also inhibited by the proteins of human papilloma virus
- this is the most often mutated gene in spontaneous human cancers
- other common anti-oncogenes
- p16INK4 is a cell-cycle gene which is very commonly deleted in lots of cancers; it may function as an oncogene or anti-oncogene
- all renal cell carcinomas have lost the Von Hippel-Landau locus; oat cell carcinomas also lack a portion of 3p; all otehr lung cancers lack a smaller chunk in the same place
- people heterozygous for a deletion of a bit of 11p have andridia, and they develop Wilms' tumors which are homozygous for the deletion
- Von Recklinghausen's disease type I patients are heterozygous for a deletion on chromosome 17, named NF-1, and its protein product, neurofibromin characterized as a facilitator of hydrolysis of GTP by normal ras p21
- Von Recklinghausen's disease type II patients are heterozygous for a loss of a tiny bit of chromosome 22, and their tumors are homozygous for this loss
- colon cancers typically become homozygous for deletions of 5p and 5q21
- mutations on either chromosome 11 (multiple endocrine neoplasia I) or chromosome 10 (multiple endocrine neoplasia II) make people susceptible to various endocrine tumors
- when a cancer cell and a non-cancer cell are fused, the product is often a non-cancer cell
- the phakomatoses are anti-oncogene deletion syndromes that affect the brain
Effects of benign tumors on the patient
- some benign tumors cause serious problems because of their location:
- pituitary adenomas crushing the normal pituitary and optic nerves
- craniopharyngiomas destroying the hypothalamus
- meningiomas compressing the brain
- colloid cysts blocking the flow of cerebrospinal fluid
- pleomorphic adenoma of the salivary gland encasing the facial nerve
- too many tumors
- hormone production
- GI problems
- large size
- torsion and infarction
Effects of malignant tumors on the patient
- brain damage and herniation
- pumonary edema - blocking pulmonary lymphatics
- bone fractures
- thrombocytopenia, granulocytopenia, and even anemia result from bone marrow replacement by tumor; hemorrhage at many locations results from thrombocytopenia and/or vascular invasion
- bowel obstruction
- pleural effusions
- ulcers and fistulas
- advanced malignant tumors usually cause cachexia which is a poorly-understood syndrome of weakness, malaise, anorexia, and wasting
- paraneoplastic syndromes result from elaboration of substances by the tumor, and occur remote from the tumor
- fever is a common presentation
- Cushing's syndrome (too much cortisol) - is common in benign and malignant tumors of the adrenal cortex, and in oat cell carcinoma of the lung and occassionally other apudomas (produces ACTH)
- masculinization - common in certain ovarian and adrenal tumors
- feminization - means breast development in a child or man, recurrence of uterine bleeding after menopause ; it is seen most often with testicular or ovarian tumors
- low serum sodium - caused by hypersecretion of hADH is a major problem in oat cell carcinoma; in cachexia from any cause, the osmostat may be reset by protein wasting and sodium lowered for this reason
- high serum calcium - due to bony metastases from any tumor, or from parathyroid like substances produced by squamous cell carcinoma of the lungs
- hypoglycemia - can result from insulinomas and rarely rom other tumors; causes obesity, fells terrible, and can kill
- carcinoid syndrome - results from production of serotonin and knins by certain apudomas
- erythrocytosis - seen whenever a renal cell carcinoma produces excessive erythropoietin
- thrombocytosis - poorly-understood, common finding in cancer; usually the increase in platelets is mild
- autoimmune hemolytic amenia
- hyperviscosity syndrome - results from cancers that elaborate IgM; the very thick blood sludges in the brain and death results
- peripheral neuropathy - very common paraneoplastic syndrome, and it appears in an adult without an obvious explanation, a search for cancer is always indicated
- CNS syndromes - may result from metastases, electrolyte disturbances, infections, or autoimmunity
- Eaton-Lambert - a myasthenia gravis like NMJ problem seen is some lung cancers; patients make an autoantibody against calcium channels that blocks release of Ach
- acanthosis nigricans - an accumulation of black hyperkeratotic papules in the armpits and groin
- dermatomyositis-polymyositis
- clubbing of the digits - commonly from lung cancer
- venous thrombosis - marker for pancreatic cancer
- DIC - common in advanced cancer
- marantic endocarditis - little fibrin vegetations on the heart valves seen in patients with any wasting disorder
- myasthenia gravis, immune destruction of normoblasts, and supression of plasma cells are all common in thyomas
- plugging of the renal tubules by immunogolbulin light chains is common in cancer of plasma cells
- glomerular protein leakage is a troublesome effect of various cancers
- what causes pain?
- invasion of bone, causing microfractures is probably the most common mechanism of pain
- obstruction of a hollow organ
- infiltration of nerve plexuses - pancreatic cancer invading celiac plexus
- psychological distress
- what finally kills the patient?
- pneumonia is the common pathway out of life for many cancer patients; part of the problem is neutropenia and/or non-specific immunosuppression caused by cancer
- tumor nodules in the lung obstruct the airways, pleural effusions and just lying in bed cause atelecasis (collapse of the alveoli, which get infected easily), cachectic patients are too weak to cough to keep their aiways clean, bed-ridden patients aspirate food and vomitus, and narcotics suppress respiratory drive and cough
- sepsis is common
- hemorrhage is common in the thrombocytopenia patient
- pulmonary thromboemboli kill many bedridden cancer patients
- renal failure
- paraneoplastic syndromes are highly lethal
- iotragenic disease
- suicide and active euthanasia account for an unknown percentage of deaths in cancer patients
Tumor Immunology
- for some cancers, a dense infiltration of lymphocytes imparts a slightly better prognosis, but this is hardly decisive
- reinfusion of lymphocytes has caused some regression of the tumor
- people who are immune crippled simply don't have increased rates for any common cancers
- the malignant lymphomas that are result from immunosupression arise from cells that are already undergoing compensatory hyperplasia because of immunosupression
- Kapsoi's sarcoma is not cancer
- squamous cell carcinomas of the lower lip probably have some more mundane cause than "escape from immune surveillance"
- nude mice have no cellular immunity but are no more susceptible to spontaneous cancers than any other mice
- tagging antibodies against antigens with pseudomonas exotoxin selectively destroy cancer cells
Cancer Epidemiology
- a tremendous number of chemical compunds are carcinogens
-1) we are not dying in youth of violence, infection, malnutrition, or obstetrical catastrophes, but are living long enough to get cancer
2) primitive societies do not always make the diagnosis of cancer when it strikes
- incidences of various cancers is changing in our country and around the world
- lung cancer is increasing
- stomach cancer is now rare
- cancer of the pancreas and kdney and leukemia are becoming somewhat more common in both sexes
- cancer of the uterus is becoming less common
- malignant lymphoma is becoming more common, probably due to sunbathing
- breast cancer is less common in the third world countries
- U.S. leads in colon cancer
- Japanese men seldom get prostate cancer
- cancer of the esophagus is the major killer in China
- Japan has a high rate of atrophic gastritis and stomach cancer
- Burkitt's lymphoma is an African disease, and its distribution corresponds to where malaria is endemic
- skin cancers are more common in light-skinned people
- cancer of uterine cervix is rare where men are circumscribed
- blacks almost never get cancer of the testis
- some cancers have strong or weak tendencies
- adenocarcinoma in the colon is an autosomal dominant trait
- autosomal dominant
- familial polyposis
- Gardner's syndrome
- multiple endocrine neoplasia
I - pituitary, parathyroids, pancreatic islets
II - parathyroids, medullary thyroid CA, pheochromocytoma
IIb - like II - but parathyroid involvement is less common, and ganglioneuromas stud the GI tract
- Peutz-Jeghers
- retinoblastoma
- Von Hippel-Lindau syndrome
- Von Recklinghausen's neurofibromatosis
- Li-Fraumeni syndrome - suspect a p53 mutation whenever a young person has developed two different cancers
- breast and ovary cancer
- familial melanoma
- Lynch's familail non-polyposis colon cancer
- tuberous sclerosis
- autosomal recessive
- ataxia-telangiectasia
- Fanconi's anemia
- Bloom's syndrome
- xeroderma pigmentosa
- Werner's syndrome
- Von Recklinghausen's neurofibromatosis
- 1 in 3000
- variable expressivity, but nearly complete penetrance
- type I - loss of an effective anti-oncogene
- type II - caused by loss of a similar gene
- patients have nerve tumors anywhere, and pigmented skin lesions
- include schwannomas and plexiform neurofibromas; the elephant man's skin was caused by epidermal and dermal hyperplasia overlying neurofibromas
- often the diagnosis of neurofibromatosis is not obvious at birth; it will declare itself with time
- pheochromocytomas are tumors of the adrenal medulla or similar masses of chromaffin, neuron-like tissue
- Von Hippel-Lindau disease
- the deleted anti-oncogene seems is at 3p25, which is regularly deleted in renal cell carcinomas; locus is named VHL
- these patients may have a variety of other curious tumors and cysts
- tuberous sclerosis
- 1 in 2000
- multiple tumors and widely variable penetrance
- include
- adenoma sebaceum
- candle gutterings (benign glial nodules on the walls of the cerebral ventricles)
- rhabdomyomas of the heart
- angiomyolipomas
- various brain tumors
- most patients are dull or mentally retarded, and many have seizures
- autosomal dominant with variable penetrance and a high rate of sporadic cases; the genetics remain uncertain
Tumor markers
- substances produced by cancer cells, which when elevated in the serum assist in the diagnosis of cancer
- Ig light chains - plasma cell myeloma, other B-cell tumors
- carcinoembryonic antigen - various carcinomas
- alpha-fetoprotein - hepatocellular carcinoma, embryonal cell carcinoma of testis/ovary
- hCG - placental and certain testicular carcinomas
- calcitonin - medullary carcinoma on the thyroid
- postatic acid phophatase - prostate cancer
- prostate specific antigen - prostate cancer
- CA-125 - ovary cancer
- CA-19-9 - pancreatic cancer
- carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP) are oncofetal antigens - they are major proteins in fetuses that the body stops making around the time of birth
Cancers arising from pre-existing tumors
- glioblastoma multiforme - arises from low-grade astrocytoma
- colon cancer - almost always arises from a benign colonic polyp
- poorly differentiated granulocytic leukemia - the typical fatal event in well-differentiated granulocytic leukemia; this is the infamous blast crisis
- aggressive leukemia/lymphoma - supervening on that most indolent of systemic cnacers, chronic lymphocytic leukemia, is the infamous Richter's syndrome; and aggressive lymphomas often arise from low-grade, indolent, follicular B-cell lymphomas
- plasma cell myeloma - often arises in the setting of longstanding benign monoclonal gammopathy; the latter is a quasi-benign clonal plasma cell proliferation
- anaplastic carcinoma of the thyroid gland arises from pappillary of follicular thyroid cancer
- yolk-sac cancer - often arises in a benign teratoma (especially the familiar sarcococcygeal teratomas of newborns)